Selective activators of the mGluR5 subtype metabotropic glutamate receptor (mGluR) have been proposed as a novel approach for treatment of schizophrenia. Unfortunately, previous efforts to develop highly selective mGluR5 agonists have failed because of the high conservation of the orthosteric glutamate binding site across all mGluR subtypes. We have now developed highly selective activators of mGluR5 that have no activity at any other mGluR subtype. The key to achieving this unprecedented selectivity was to target allosteric sites on mGluR5 rather than developing traditional agonists acting at the highly conserved glutamate binding site. The prototypical mGluR5 positive allosteric modulators (PAMs) do not activate mGluR5 directly but potentiate the response of the receptor to glutamate. These mGluR5 PAMs potentiate mGluR5-mediated responses in multiple neuronal populations and our preliminary studies suggest that mGluR5 PAMs have activity in rodent models that are used to predict antipsychotic efficacy. In addition, we have shown that mGluR5 PAMs enhance hippocampal synaptic plasticity and our preliminary studies reveal that mGluR5 PAMs enhance at least one form of hippocampal-dependent learning in rodents. These studies suggest that mGluR5 PAMs may provide efficacy in treatment of both positive symptoms and cognitive disturbances in schizophrenia patients. We have now discovered a range of structurally and functionally distinct mGluR5 PAMs that have excellent pharmacokinetic profiles and brain penetration for use in behavioral studies. In addition, we have developed mGluR5 PAMs that have distinct modes of efficacy. These include the prototypical pure allosteric potentiators that have no effects in the absence of glutamate, and other compounds that have allosteric agonist activity and fully activate mGluR5 in the absence of glutamate. It is possible that these new mGluR5 allosteric agonist/potentiators will have advantages or disadvantages to pure allosteric potentiators in vivo. However, at present, allosteric agonist activity has only been established in recombinant systems and it is not clear whether allosteric agonist activity will be observed when measuring multiple functional responses to mGluR5 activation in native systems. Also, the effects of mGluR5 PAMs that have these two modes of efficacy (pure potentiators versus allosteric agonist/potentiators) have not been rigorously evaluated in a broad range of animal models designed to assess potential antipsychotic activity and efficacy in improving different domains of cognitive function. Thus, we will perform a series of studies to systematically test the hypothesis that these novel compounds regulate mGluR5 signaling in brain circuits thought to be important for their potential therapeutic effects. In addition, we will test the hypothesis that mGluR5 PAMs have efficacy in a range of animal models that predict antipsychotic and cognition-enhancing effects and will directly compare the effects of pure allosteric potentiators versus mGluR5 allosteric agonist/potentiators. PUBLIC HEALTH RELEVANCE: Studies in patients suffering from the schizophrenia suggest that drugs that selectively activate a specific receptor for the neurotransmitter glutamate may provide a novel approach for treatment of this debilitating brain disorder. We have discovered new drug like molecules that selectively activate this neurotransmitter receptor. Studies are proposed to test the hypothesis that these novel molecules have actions that predict efficacy in treatment of schizophrenia.